摘要
神经系统疾病的病因及病理机制复杂且研究难度大,靶点发现及相应的药物研发困难.随着基因组及转录组测序等技术的发展,有关神经系统疾病的遗传形式、非遗传性或散发性神经系统疾病的靶点发现及分子机制取得了有效进展.基于转录组靶点发现的小核酸药物研发为神经系统疾病的新药开发领域提供了一种新的思路.反义寡核苷酸药物属于小核酸药物的一种,相比于以蛋白为靶点的传统小分子药或抗体药物,靶向mRNA的反义寡核苷酸具有候选靶点范围大、药物靶点筛选快、研发成功率高等优点.目前,反义寡核苷酸药物在神经退行性疾病领域的治疗广受各药物研发企业重点关注,具有良好临床应用前景.本研究总结反义寡核苷酸药物在多种神经系统疾病治疗中的研究与应用,回顾其作用机制、研发优势以及结构修饰方法的发展,并探讨用于治疗神经系统疾病的反义寡核苷酸药物临床用药及研发的最新进展,旨在为神经系统疾病、尤其是罕见病及难治病的新药研发提供借鉴和参考.
Abstract
The etiology and pathological mechanisms underlying nervous system diseases are intricate,posing challenges in pinpoint-ing drug targets for the development of novel therapeutics.Advances in genome and transcriptome sequencing,along with other techno-logical innovations,have facilitated significant strides in uncovering targets and molecular pathways implicated in genetic,non-hereditary,or sporadic nervous system disorders.The emergence of small nucleic acid drugs,based on transcriptome-target discovery,represents a promising avenue for addressing these diseases.Among these,antisense oligonucleotide(ASO)constitute a subclass of small nucleic acid drugs.ASO,which target mRNA,offer several advantages over traditional small molecule or antibody-based therapies that target proteins,including a broad spectrum of candidate targets,expedited target screening,and a heightened success rate in drug development.At present,the treatment of ASO drugs in the field of the realm of nervous system disorders is widely concerned by numer-ous pharmaceutical research and development enterprises,and ASO drugs has a good prospect of clinical application.This review summa-rizes the research and clinical applications of ASO in treating diverse nervous system pathologies,elucidating their mechanism of action,developmental advantages,structural modification methodologies,and the latest advancements in clinical application for the treatment of nervous system diseases,to provide reference for the research and development of new drugs for neurological disorder,especially for rare and refractory diseases.
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